Estrogen level decreases in post-menopausal women have been shown to increase the risk of memory loss and Alzheimer's disease. While these effects might be mitigated using hormone replacement therapy, traditional estrogen-based hormone therapies also lead to increased risk of cancer, heart disease and stroke. These adverse effects are mediated predominantly by estrogen receptor-alpha (ER?). Relevant to menopause, aging significantly reduces levels of ER? and ER? in the hippocampus, suggesting an association with age-related memory decline; but, ER? remains the predominant isoform. We hypothesize that an optimal treatment for age-related memory decline in post-menopausal women may be via treatment that selectively activates hippocampal ER?, thereby avoiding the adverse effects of ER? agonists. But, current ER? agonists have only modest selectivity for the beta versus alpha isoform, so present some cancer risk. Therefore, there is a need for more potent and selective ER? agonists, as potential treatments for postmenopausal age-related memory decline. The objective of this project is to develop and characterize a new class of highly selective ER? agonists, to treat postmenopausal age-related memory decline. This includes computational design, synthesis, in vitro testing, and in vivo efficacy measurements of ER? analogs based on a novel compound we have recently reported. We will use this new class of compounds to test our hypothesis that selective ER? agonists are an effective therapeutic intervention for treatment of postmenopausal memory decline, with minimal potential for adverse effects - including cancer. Our Aims Are to: 1. Design, synthesize and test cycloheptane-hydroxymethane ER? agonists in vitro. Perform computational optimization of our lead compound using docking, bioisostere and ligand-based methods, followed by synthesis and testing of compounds predicted to bind with highest affinity and selectivity. 2. Optimize in vitro ADME properties of the cycloheptane-hydroxymethane ER? agonists. Test for CYP450 metabolism and inhibition (CYP3A5, CYP2D6, CYP2C8/9, CYP1A2), as well as hERG binding and intestinal transport, modeled using a Caco assay. Synthesize and test analogs to optimize for improved in vitro ADME properties, while retaining high affinity and selectivity for ER?. 3. Determine efficacy of ER? agonists for cognitive enhancement in an appropriate mouse model. In ovariectomized mice, determine effect of the top 3 compounds on hippocampal memory consolidation using a novel object recognition assay. Effect on the estrogen-based activation of the ERK/MAPK cascade will also be assessed.